The Size of the Proteasomal Substrate Determines Whether Its Degradation Will Be Mediated by Mono- or Polyubiquitylation

Shabek, Nitzan; Herman-Bachinsky, Yifat; Buchsbaum, Samuel; Lewinson, Oded; Haj‐Yahya, Mahmood; Hejjaoui, Mirva; Lashuel, Hilal A.; Sommer, Thomas; Brik, Ashraf; Ciechanover, Aaron

doi:10.1016/j.molcel.2012.07.011

Cited by 146 publications

(141 citation statements)

References 53 publications

(70 reference statements)

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“…K48-linked ubiquitin chains of four or more were once thought to be essential for proteasome-mediated degradation of a substrate (50). A more recent study, however, indicates that chain length requirements depend upon the size of the substrate, with smaller substrates requiring shorter chains (51). In our experiments, we primarily observed Grim-ubiquitin chains of two to four ubiquitins in length (Grimubiquitin 2-4 ; Figs.…”

Section: Drice Removes the C Terminus From Grim-ubiquitin Conjugates Andmentioning

confidence: 68%

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Yeh¹,

Bratton²

2013

Proc. Natl. Acad. Sci. U.S.A.

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Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1's RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the lysine necessary for ubiquitinylation as well as any existing ubiquitin conjugates. Cleavage therefore enhances the stability of Grim and initiates a feed-forward caspase amplification loop, resulting in greater cell death. In summary, Grim is a caspase substrate whose cleavage promotes apoptosis by limiting, in a target-specific fashion, its ubiquitinylation and turnover by the proteasome.

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Section: Drice Removes the C Terminus From Grim-ubiquitin Conjugates Andmentioning

confidence: 68%

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Yeh¹,

Bratton²

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, several studies have shown the crosstalk between ubiquitination and other post-translational modifications, including phosphorylation and acetylation, thereby increasing the complexity of this signaling network (Beltrao et al, 2012). Surprisingly, in some cases, mono-and multi-monoubiquitination can also act as proteasomal degradative signals (Guterman and Glickman, 2004;Boutet et al, 2007;Dimova et al, 2012;Shabek et al, 2012).…”

Section: Ubiquitinmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

110

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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“…Finally, it has recently been shown that small proteins, less than 150 amino acids, can be degraded by monoubiquitination (25) so that it is possible that p12 is also degraded in vivo directly after monoubiquitination by CRL4…”

Section: Resultsmentioning

confidence: 99%

Degradation of p12 Subunit by CRL4Cdt2 E3 Ligase Inhibits Fork Progression after DNA Damage

Terai

Shibata

Abbas

et al. 2013

Journal of Biological Chemistry

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Background:The mechanism for inhibiting fork progression after DNA damage still remains. Results: CRL4Cdt2 promotes the degradation of the p12. Cells expressing a stable form of p12 exhibit UV-resistant DNA synthesis and decreased inhibition of fork progression. Conclusion: p12 degradation by CRL4Cdt2 is critical for inhibiting fork progression. Significance: p12 degradation is one mechanism by which DNA damage in S-phase cells inhibits fork progression.

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The Size of the Proteasomal Substrate Determines Whether Its Degradation Will Be Mediated by Mono- or Polyubiquitylation

Cited by 146 publications

References 53 publications

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Degradation of p12 Subunit by CRL4Cdt2 E3 Ligase Inhibits Fork Progression after DNA Damage

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